Bicistronic AAV Vectors for CNS Co-Delivery of HEXA and HEXB
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Solution Overview
Problem
Current treatments for Tay-Sachs and Sandhoff diseases, which result from hexosaminidase A deficiency, are inadequate, and delivering separate vectors for alpha and beta-subunits of hexosaminidase is inefficient due to low co-infection likelihood in the CNS, compromising efficacy.
Innovation Solution
Development of recombinant AAV vectors encoding both hexosaminidase alpha and beta-subunits in a bicistronic configuration, allowing simultaneous expression and overcoming the limitations of separate vector delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If separate AAV vectors are used to deliver alpha and beta-subunits, then each subunit can be delivered independently, but the co-infection likelihood in the CNS is low, compromising therapeutic efficacy
Solution Approach 1:
The patent combines two separate AAV vectors into a single bicistronic vector that simultaneously delivers both the alpha-subunit (HEXA) and beta-subunit (HEXB) coding sequences. This merging ensures that both subunits are co-delivered to the same CNS cells, resolving the low co-infection likelihood problem while maintaining independent expression control through separate promoters for each subunit
2Reliability
If a single AAV vector encodes both hexosaminidase alpha and beta-subunits, then co-delivery and simultaneous expression are achieved, but the vector design complexity increases
Solution Approach 1:
The bicistronic vector design segments the expression control by using separate promoters (such as U6 or H1 for alpha-subunit and CMV or CBA for beta-subunit) for each coding sequence. This segmentation allows independent regulation of each subunit's expression while maintaining a compact single-vector structure, thus managing design complexity through modular promoter-coding sequence units
3Ease of manufacture
If current treatments are used for Tay-Sachs and Sandhoff diseases, then existing therapeutic approaches are applied, but they are inadequate and do not address the root cause of hexosaminidase A deficiency
Solution Approach 1:
The patent uses AAV vectors as intermediary delivery vehicles to introduce functional HEXA and HEXB coding sequences into the CNS of patients with hexosaminidase A deficiency. These viral vectors act as mediators that transport the therapeutic genetic material across the blood-brain barrier and into target cells, enabling gene replacement therapy that directly addresses the enzymatic deficiency rather than treating symptoms
Data Source
AI summary
Aspects of the disclosure relate to bicistronic AAV nucleic acid constructs comprising a transgene encoding hexosaminidase A (HEXA) and hexosaminidase (HEXB) proteins. In some embodiments, the disclosure provides methods for treating or preventing lysosomal storage disorders, such as Tay-Sachs disease and Sandhoff disease, using bicistronic nucleic acid constructs described by the disclosure.